The A2 peptide is widely thought to be implicated in the pathogenesis of Alzheimer's Disease (AD) and A2-lowering strategies are being pursued by most major pharmaceutical companies. Archer Pharmaceuticals Inc. (Archer) and the Roskamp Institute have jointly developed A2-lowering drugs which indirectly inhibit BACE and reduce amyloid accumulation whilst preserving cognitive function in transgenic models of the disease. The lead series is based on a calcium channel blocking drug, nilvadipine, for which preliminary data suggests efficacy in delaying cognitive decline and in preventing the transition from mild cognitive impairment to AD. The potential efficacy of nilvadipine has been demonstrated in a Phase I/lla trial completed by Archer in Europe and supporting clinical data from independent studies. Despite this, and a wealth of preclinical and safety data, there are concerns that increasing doses of nilvadipine to improve efficacy will be limited by its anti-hypertensive effects. Therefore, we have examined the non anti-hypertensive (-)-nilvadipine enantiomer in preclinical models and have shown that it also lowers A2/amyloid levels in acute paradigms in transgenic models of the disease. In advancing this form of nilvadipine as a lead compound there are critical data required for the development of clinical trials. Although racemic nilvadipine is known to concentrate in the brain in man, key factors that will determine the relative brain concentrations of (-)-nilvadipine that can be achieved in man are: a) Greater [times three] metabolism of (-)-nilvadipine vs. (+)-nilvadipine in man;b) Increased AUCbrain/ AUCplasma ratios for (-)-nilvadipine vs. racemic nilvadipine [3:1] in rodents and;c) Much lower [100 fold reduced] vasodilatory effects of (-)-nilvadipine vs. (+)-nilvadipine. This phase I proposal will address the following issues: Aim 1 will correlate plasma levels (PK) of (-)- nilvadipine with brain PK and the impact on A2 levels (PD) in transgenic mouse models of AD. It will also compare the impact of acute vs. chronic delivery profiles on brain PK and PD in the same models. Finally, the impact of increasing doses of (-)-nilvadipine on brain PK/PD will be compared to racemic nilvadipine and the highest non-toxic dose determined and basic toxicology data gathered. Aim 2 will explore the impact of 6 months of treatment with (i) (-)-nilvadipine compared to racemic nilvadipine at the highest non-toxic dose of the latter, and (ii) the highest non-toxic (-)-nilvadipine dose, in a transgenic model of AD with pathological and behavioral outcomes. This phase I proposal is intended as a prelude to a phase II plan to delineate toxicology parameters, synthetic and formulation strategies (both of which are already developed to non-GMP levels by Archer) with a view to an IND filing on (-)-nilvadipine for clinical trials for use in AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD), the most common form of dementia, affects over 27 million people worldwide and this rate is expected to double by year 2050. In the United States, Medicare and Medicaid costs for AD amount to over $140 billion dollars per year and the burden on Public Health is anticipated to increase sharply as the population ages. Currently, there are no effective disease modifying therapeutics for AD and we wish to develop a novel derivative of nilvadipine which demonstrates encouraging preclinical data in models of the disease.